Biochemical evidence indicates that brain norepinephrine (NE) utilization is increased by stress-inducing stimuli. Brain areas whose sole NE innervation arises from the locus coeruleus (LC) show such increases, suggesting LC neurons are activated during stress. The proposed studies will test this prediction by recording from individual LC neurons in rats and monkeys and will examine whether LC activation is mediated by corticotropin-releasing factor (CRF), the neurohormone that induces release of adrenocorticotropin-releasing hormone from the pituitary during stress. It has been hypothesized that CRF neurons and fibers localized within the brain, including the LC, mediate behavioral and autonomic responses to stressful stimuli. Preliminary results presented here show exogenous CRF increases LC discharge rates in anesthetized rats. The proposed studies have the following aims: 1) To determine whether exogenous CRF increases the discharge rates of LC neurons. The effects of ventricular and local application of CRF on spontaneous and stimulus-elicited LC activity will be tested in anesthetized and unanesthetized rats and monkeys. 2) To determine, in rodents and primates, the detailed distribution of CRF-immunoreactive neurons and fibers in the LC region. The possible anatomical substrate for CRF effects on LC and nearby neurons will be examined. 3) To more fully characterize LC responses to stressful and neutral sensory stimuli and determine whether they are blocked or modified by CRF antagonists or antibodies. These studies will test the role of endogenous CRF in controlling LC activity. 4) To more fully characterize the receptor and mechanisms by which CRF acts on LC neurons. The possibility that CRF acts on LC by local ACTH release will be investigated by microapplication of ACTH and CRF to LC neurons in the absence and presence of an ACTH antagonist. The structural requirements for CRF effects will be determined using CRF analogues. This and other tests will characterize the LC CRF receptor and its similarity to the pituitary CRF receptor. In summary, these studies will characterize LC responses to stress-inducing stimuli and determine the effects of CRF, a critical initiator of stress responses, on LC. The anatomical basis for CRF/LC interactions will be examined. The determination of a functional physiological relationship between CRF and LC will elucidate the operation of two CNS systems which are anatomically, chemically, and physiologically characterized and involved in stress responses.